Electrophilic Reactivities of Vinyl p-Quinone Methides.

The electrophilic reactivity of a series of 8-arylated vinyl p-quinone methides (pVQMs) was determined by analyzing the kinetics of their reactions with carbanions in DMSO at 20 °C according to the linear free energy relationship log k = sN(N + E). The electrophilicity parameters E for pVQMs were used to successfully predict Michael-additions with structurally diverse C-, N-, S-, and H-nucleophiles.

The interest in vinyl p-quinone methides (pVQMs)[1−4] increased recently because it was shown that applying a 1,6-addition/cyclization strategy in reactions of pVQMs with sulfonium ylides,[5] carbanions,[6] or ammonium ylides[7a] gave rise to vinyl cyclopropanes that rearranged to chiral spirocyclopentenes. Hence, pVQMs are versatile building blocks for the stereocontrolled synthesis of complex molecules.[5−7] The further development of pVQM-based organic synthesis could clearly benefit from the knowledge of their electrophilic reactivity to define scope and limitations of their reactions with nucleophiles.[1−3]

The electrophilicity of 6-aryl-substituted p-quinone methides (pQMs) had been studied by Mayr and co-workers[8] who analyzed the second-order rate constants of the reactions of nucleophiles with pQMs according to the linear free energy relationship eq :[9]

In this work, we set out to characterize the electrophilic reactivity E of pVQMs 1a–d (Figure ) by studying the kinetics of their reactions with the carbanions 2a–d as reference nucleophiles in DMSO at 20 °C. In this way, pVQMs are integrated into Mayr’s reactivity scales, which allows chemists to reliably predict the scope of their reactions with structurally diverse nucleophiles when exploring novel organic syntheses.[10]

Figure 1

pVQMs 1a–d and reference nucleophiles 2a–d used for the determination of their electrophilicities E. Nucleophilicity parameters N and sN (in DMSO) were obtained from previous literature.[8a,11]

The pVQMs 1a–d were synthesized according to literature procedures and characterized by spectroscopic and electrochemical methods (Supporting Information). Single crystal X-ray crystallography (Figure ) revealed that the conjugated π-systems in 1a–d are slightly bent. The pVQMs 1a–d are dyes with λmax between 405 and 432 nm (in DMSO) and molar absorption coefficients in the range of 5 × 104 M–1 cm–1 (Figure ), which enabled us to follow their reactions with the colorless nucleophiles 2a–d by photometry.

Figure 2

Single crystal X-ray structures of the pVQMs 1a–d. Thermal ellipsoids are shown at a 50% probability level. Bottom: Side views on 1a–d. The blue lines indicate the planes through the carbon atoms of the quinone moieties.

When solutions of the colored pVQMs 1 in DMSO (or d6-DMSO) were treated with the potassium salts of nucleophiles 2, a rapid fading of the color of 1 was observed. As described in Scheme , the reaction mixtures were then either analyzed by NMR methods or worked-up to isolate the Michael adducts. Mixtures of the regioisomers 3 and 4 were obtained via 1,6- and 1,8-additions of 2a, 2c, and 2d to pVQMs 1, which are ambident electrophiles. Only 2b underwent selective 1,8-additions to 1a–d, and the exclusive formation of regioisomers 4 could be detected in the crude reaction mixtures. Subsequent acidic workup of the reaction mixtures yielded the isolated products in good to excellent yields.

Scheme 1

Products of the Reactions of 1 with 2 in DMSO

Yields of isolated products after chromatographic workup.

Reaction performed in d6-DMSO; the initially formed potassium phenolates 4Xb-K were directly analyzed by NMR spectroscopic methods.

Reaction at 1 mmol scale.

Reaction performed in d6-DMSO; the mixture of potassium salts 3bc-K and 4bc-K (both with deprotonated malononitrile moiety) was directly analyzed by NMR spectroscopic methods.

In the kinetic experiments the presence of a Brønsted acid is required to ensure fast protonation of the initial Michael adducts.[8a] Solutions of the corresponding CH acids 2-H in DMSO were therefore only partially deprotonated by 0.5 equiv of KOtBu to generate DMSO stock solutions of the carbanions 2 as 1:1 mixtures with the CH acids 2-H. The reaction kinetics were determined by employing stopped-flow UV/vis photometry to follow the fading of the colored pVQMs 1 in their reactions with the colorless carbanions 2. By using a large excess of the carbanions over the electrophiles, the resulting absorbance decays followed first-order kinetics. First-order rate constants kobs were calculated by least-squares fitting of the single-exponential At = A0 exp(−kobst) + C to the experimentally observed time-dependent absorbances (Figure a). Second-order rate constants k2exptl were subsequently obtained as the slopes of the linear correlations of kobs with the concentrations of the carbanions [2] (Figure b; analogous correlations for all other electrophile–nucleophile combinations studied in this work are shown in the Supporting Information). Table gathers the measured k2exptl values for the investigated reactions of pVQMs 1 with the carbanionic reference nucleophiles 2.

Figure 3

(A) Decay of the absorbance A of 1c (c = 1.75 × 10–5 M) at 408 nm in the reaction (DMSO, 20 °C) with 2b (c = 6.00 × 10–4 M). (B) The slope of the linear correlation of kobs with the concentration of 2b yields the second-order rate constant k2.

Table 1

Second-Order Rate Constants for the Reactions of 1 with the Reference Nucleophiles 2 in DMSO at 20 °C

1	2	k2exptl (M–1 s–1)	k2eq 1,a (M–1 s–1)	k2exptl/k2eq 1
1a	2a	5.72 × 102	3.59 × 102	1.6
	2b	7.88 × 101	6.62 × 101	1.2
	2c	3.09 × 101	2.98 × 101	1.0
	2d	1.06 × 101	2.00 × 101	0.53
E(1a) = −17.42
1b	2a	7.11 × 102	6.49 × 102	1.1
	2b	1.65 × 102	1.23 × 102	1.3
	2c	6.16 × 101	5.65 × 101	1.1
	2d	2.39 × 101	3.79 × 101	0.63
E(1b) = −17.00
1c	2a	1.14 × 103	8.21 × 102	1.4
	2b	2.28 × 102	1.58 × 102	1.5
	2c	7.44 × 101	7.30 × 101	1.0
	2d	2.47 × 101	4.88 × 101	0.51
E(1c) = −16.84
1d	2a	3.44 × 103	1.91 × 103	1.8
	2b	5.92 × 102	3.82 × 102	1.5
	2c	1.66 × 102	1.82 × 102	0.91
	2d	5.08 × 101	1.22 × 102	0.42
E(1d) = −16.25

Second-order rate constant k2 by applying eq .

Next, we used eq to perform a least-squares analysis, which allowed us to determine the electrophilicity parameters E for the pVQMs 1a–d from k2exptl and the known nucleophilicity parameters N (and sN) of the reference nucleophiles (Table and Figure S1, Supporting Information).

If compared to the analogously substituted pQMs the electrophilicity of pVQMs 1 is reduced by 1–2 orders of magnitude (Figure ).[8] Moreover, electronic substituent effects have a stronger impact on the electrophilicity of pQMs than on analogous π-extended pVQMs: While a change from a methoxy- to a nitro-substituent in pQMs increases their electrophilicity E by 1.7 units,[8b] the same change in the series of pVQMs results in an increase of E by only 0.9 units.[12] This might be rationalized by the observed deviations from planarity in the solid state structures (Figure ), which weaken the conjugation and thus attenuate the substituent effects.[13]

Figure 4

Comparison of electrophilicities E of pVQMs 1 with those of analogously substituted pQMs.[8] Gray values are interpolated on the basis of the Hammett correlation described in ref (8b).

Quantum-chemical calculations were performed to gain a deeper understanding of the ambident reactivity of pVQMs. We calculated the Gibbs activation and reaction energies for the addition of nucleophiles 2b and 2d to the electrophile 1b at the M06-2X/6-31+G(d,p) level considering solvation by the SMD solvation model for DMSO (Figure ).[14] In line with our experimental results and previous reports on the formation of regioisomeric mixtures upon concomitant attack of different types of nucleophiles at 1,6- and 1,8-positions of simple vinyl p-quinone methides,[1c,3] the calculations show that the barriers for 1,6- and 1,8-addition differ only by 4–8 kJ mol–1. For a given combination of 1 and 2, also both intermediates P1(1,6) and P1(1,8) are formed with similar Gibbs reaction energies.

Figure 5

Reaction paths for additions of the nucleophiles 2b (Acc = CO2Et) and 2d (Acc = CN) to pVQM 1b (calculated at the SMD(DMSO)/M06-2X/6-31+G(d,p) level of theory).

Depending on the acidity of the (Acc)2CH moiety, the initially formed phenolate group in the adduct P1 might be protonated to yield the corresponding phenol P2. In line with NMR spectroscopic studies of the reactions (Supporting Information), the proton transfer is unfavored for 2b (pKaH 18.7 for (EtO2C)2MeC–)[15] and the phenolate form P1(1,8) persists as detectable species in the reaction mixture (pKaH 17.7 for 2,6-tert-butyl-4-methylphenolate).[16] In additions of 2d (pKaH 12.4 for (NC)2MeC–)[17] to pVQMs, proton transfer from C–H to O–H occurs to yield a phenol. Owing to the energetic similarity of the competing reaction paths, the observed regiochemistry (1,6- vs 1,8-attack) for the attack of nucleophiles at pVQMs does not follow a clear pattern but seems to depend on subtle effects, which are introduced by the nature of the nucleophile.

Nevertheless, the determined electrophilicity parameters E for 1a–d can be used to rationalize reported reactions and, more intriguingly, to predict new reactions. In Figure , the electrophilicity and nucleophilicity scales are arranged such that (E + N) = −3. Reaction partners on the same horizontal level react (somewhat dependent on the sN parameter) with second-order rate constants of 10–3 to 10–2 M–1 s–1 at 20 °C. Accordingly, reactions of pVQMs 1 with sulfonium ylides, such as 12, and α-bromo malonate (N determined for the chloro-derivative 6) have been described in the literature.[5,6] Nucleophiles located at levels below that of the pVQMs can be expected to react even more rapidly.

Figure 6

Ranking of pVQMs 1a–d in the Mayr reactivity scales (nucleophilicities N in DMSO if not mentioned otherwise).[10]

Based on the prediction that reactions of 1 with nucleophiles of N > 13 should occur at 20 °C,[18] we studied the reactions of pVQMs 1 with carbanions (11 and 15), the pyridinium ylide 14, the heteroatom nucleophiles MeS– and pyrrolidine (7), and the hydride donor NaBH4 (5). For all combinations, the reaction products could be isolated in good to excellent yields without further optimization (Table ).

Table 2

Scope of pVQM (1) Reactions with Nucleophiles

As found in the initial product studies (Scheme ), different regioisomers were also observed for the reactions of 1a–d with the nucleophiles in Table : While 1,6-addition was the preferred reaction mode for NaBH4 (5), highly nucleophilic carbanions (11 and 15), and the pyridinium ylide 14, products of 1,8-attack were observed for 7 and NaSMe. We rationalize the formation of the butadienyl-substituted phenol 17 (Table , entry 2) by a cyclopropanation/ring opening sequence as previously observed for reactions of pQMs with α-halo-tosylmethyl anions.[19,20] Interestingly, the reaction of the pyridinium ylide 14 with the pVQM 1a gave the pyridinium bromide 18 (Table , entry 3), which is in contrast to reactions of ammonium ylides with pVQMs which furnish spirocyclic products.[7]

In conclusion, we have characterized the Mayr electrophilicities E of the vinyl p-quinone methides 1a–d by analyzing the kinetics and products of their reactions with carbanions in DMSO. In agreement with earlier findings on the regioselectivities of nucleophile additions to 2,6-dimethoxy-4-(2-propenylidene)-2,5-cyclohexadien-1-one and eugenol-derived vinylic p-quinone methides,[1c,3] the pVQMs 1 are ambident electrophiles that have similar 1,6- and 1,8-reactivities. While the results of our experiments do not allow us to predict the regiochemistry of the nucleophilic attack at pVQMs, the determined Mayr E parameters reliably reflect the general electrophilic reactivity of these electron-deficient π-systems. Application of the electrophilicity parameters E in eq not only rationalizes reported reactions but also empowers chemists to systematically predict novel combinations of pVQMs with nucleophiles. We demonstrated that uncatalyzed reactions of 1a–d with different types of C-, N-, S-, and H-nucleophiles with N > 14 are feasible at ambient temperature[21] and lead to novel types of conjugate 1,6- and 1,8-adducts of pVQMs.